Scientific Publications by FDA Staff

J Virol 2013 Apr;87(7):3678-86

Circulating Antibodies and Macrophages as Modulators of Adenovirus Pharmacology.

Khare R, Hillestad ML, Xu Z, Byrnes AP, Barry MA

Adenovirus serotype 5 (Ad5) naturally infects the liver after intravenous injection making it a candidate for hepatocyte-directed gene transfer. While Ad5 can be efficient, most of the dose is destroyed by liver Kupffer cells before it can reach hepatocytes. In contrast, Ad5 bearing the hexon from Ad6 (Ad5/6) evades Kupffer cells. While Ad5/6 dramatically increases hepatocyte transduction in BALB/c mice, it surprisingly had little effect in C57BL/6 mice. To determine the source of this strain-specific variation, the roles of Kupffer cells, liver sinusoidal endothelial cells (LSECs), hepatocytes, scavenger receptors, clotting factors, and immunoglobulins were analyzed. Kupffer cell numbers and LSECs, clotting factor X, and hepatocyte infectability did not vary between different strains of mice. In contrast, high levels of immunoglobulins correlated negatively with Ad5 liver transduction in different mouse strains. Removal of immunoglobulins by use of Rag-deficient mice restored Ad5 transduction to maximal levels. Removal of Kupffer cells by predosing or by testing in colony-stimulating factor knock-out mice restored Ad5 transduction in the presence of immunoglobulins. Partial reconstitution of IgM in Rag mice resulted in significant reduction in liver transduction by Ad5, but not Ad5/6. These data suggest a role for IgM-mediated clearance of Ad5 via Kupffer cells and evasion of this clearance mechanism by Ad5/6. These mechanisms may play a vital role in Ad pharmacology in animals and in humans.